Atypical chronic inflammatory demyelinating polyradiculoneuropathy: recent advances on classification, diagnosis, and pathogenesis

Purpose of review In recent years, there has been an intense debate in literature regarding the definition of the individual variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), their possible pathogenetic mechanisms, and impact in the diagnosis of CIDP. Recent findings The 2021 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines revised the definition of the individual CIDP variants and implemented their diagnostic criteria. Diagnosis of atypical CIDP is challenging and misdiagnosis is frequent, leading to diagnostic delay and consequent greater accumulation of disability and treatment dependency. Recent studies suggest that patients with typical CIDP have an antibody-mediated mechanism of neuropathy whereas in those with Lewis--Sumner syndrome (LSS) neuropathy is preferentially mediated by macrophages and T cells. Summary Although the validity of the 2021 EFNS/PNS diagnostic criteria for atypical CIDP is unknown, they will hopefully lead to greater uniformity in the selection of patients to be enrolled in future studies and to a greater diagnostic accuracy. New data are emerging on the possible pathological mechanisms of individual variants and this could result in the discovery of specific diagnostic biomarkers and new therapies.


INTRODUCTION
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neuropathy with a very heterogeneous clinical presentation. Along with a typical clinical phenotype (typical CIDP), defined as symmetric sensorimotor neuropathy involving proximal and distal segments of the four limbs with a relapsing or progressive course of at least 2 months, a few atypical variants have been described (atypical CIDP) [1][2][3][4][5][6]7 && ,8 && , . These variants include distal acquired symmetric demyelinating neuropathy (DADS), Lewis-Sumner syndrome (LSS), focal CIDP, pure motor and pure sensory CIDP. Recently a few other variants have been proposed by some authors, including chronic immune sensory polyradiculoneuropathy (CISP and CISPplus), chronic immune motor polyradiculoneuropathy (CIMP), and chronic immune sensorimotor polyradiculoneuropathy (CISMP) [41,42 & , 43,44,45 & ]. It is still unclear whether the atypical CIDP variants should be considered different phenotypes of the same disease or clinical entities with a different pathogenetic mechanism. In the recent years, an intense debate around atypical CIDP has taken place, particularly around three key issues that we will try to summarize here: the clinical boundaries of the individual variants, their weight in the diagnostic difficulty of CIDP, and their clinicopathological peculiarities.
The 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines for CIDP roughly defined the individual CIDP variants but did not provide criteria that allow to clearly establish the clinical boundaries of each of them [46]. The lack of universally recognized diagnostic criteria for atypical CIDP has favored over the years the proliferation of various definitions for the individual variants and this has resulted in a remarkable heterogeneity among studies regarding their reported frequency, clinical characteristics and response to therapy. Recently, an Italian study proposed a set of diagnostic criteria for atypical CIDP but its validity has not yet been demonstrated [7 && ]. The application of these criteria in a large cohort of patients with atypical CIDP has surprisingly shown that 53% of the patients with atypical CIDP at onset progressed to typical CIDP during the course of the disease [7 && ]. Progression to typical CIDP, however, was not absolute and a considerable proportion of patients maintained their atypical CIDP phenotype even after several years from symptoms onset [7 && ]. Transition from atypical to typical CIDP has been questioned by some authors [47] but other studies confirmed that phenotypes can change overtimes [9,34,35]. Whether this progression reflects only a greater spread of neuropathy or is instead the result of specific pathogenetic mechanisms is still to be clarified.

Distal acquired symmetric demyelinating neuropathy
In 2000, Katz et al. [1], described DADS as a distal, symmetric, sensory, or sensorimotor neuropathy sparing proximal limb, neck, and facial muscles. In their study, 60% of the patients had an IgM paraprotein and at least 33% of them were positive for anti-MAG (myelin-associated glycoprotein) antibodies [1]. Being an exclusion criterion for CIDP diagnosis, in the subsequent descriptions of DADS, only patients with negative anti-MAG antibodies were included, whereas idiopathic DADS was considered a variant of CIDP. Still, Larue et al. [3] found that 60% of the patients with DADS had a monoclonal gammopathy (40% IgG and 20% IgM). Association between DADS phenotype and IgM paraprotein was also recently confirmed in a study that has investigated the frequency and role of comorbidities in a large cohort of CIDP patients and found that 12.5% of the patients with DADS had an IgM monoclonal gammopathy (versus 5.5% of the patients with typical CIDP) [48 && ]. According to some studies, DADS is the most common variant of CIDP, with a frequency that ranges from 2 to 15% (Table 1). Although DADS is defined as predominantly distal, the exact proximal to distal gradient of motor and sensory deficits was not specified neither in the 2010 EFNS/PNS guidelines nor in their revision [46,49 && ]. Response to treatment in DADS was initially reported to be similar to that of CIDP [1,3] but subsequent studies showed that this variant is likely to exhibit a lower response to therapy [6,7 && ]. In larger cohorts, overall response to treatment and response to intravenous immunoglobulin (IVIg) in DADS was lower compared with typical CIDP [7 && ]. Most studies report DADS as a mild form of CIDP [5,7 && ,9].

Lewis-Sumner syndrome
LSS was initially defined as a sensory or sensorimotor multineuropathy with persistent motor nerve conduction blocks [11][12][13]. According to some reports, this is the most common variant of CIDP (Table 2)

KEY POINTS
There is considerable heterogeneity in the results of the various studies regarding the frequency, clinical characteristics, and response to therapy of the individual variants of CIDP, and this is at least in part explained by the lack of clear diagnostic criteria for atypical CIDP.
Diagnosis of atypical CIDP is challenging, and misdiagnosis is common and this lead to diagnostic delay, greater disability accumulation, and treatment dependency.
A greater uniformity in the selection of patients with atypical CIDP to be enrolled in the studies and an increased diagnostic accuracy are expected after the publication of the 2021 EFNS/PNS diagnostic criteria.
Validity of the diagnostic criteria for the individual CIDP variants of the EFNS/PNS remains to be evaluated and there are still areas of uncertainty in the classification of a few subgroups of CIDP patients.   ]. These figures are interesting as they show that the asymmetric form of CIDP is much more frequent than expected from a clinical entity that is considered 'atypical'. It cannot, however, be excluded that, as in vasculitic neuropathies, a certain number of patients with multineuropathic CIDP evolve over time towards an asymmetrical form. Finally, the 2021 EFNS/PNS criteria has defined LSS as a sensory or sensorimotor multineuropathy specifying that its clinical presentation is usually asymmetric [49 && ]. In 1996, Thomas et al. [25] described a form of CIDP restricted to one or two upper limbs and labelled this form 'focal CIDP'. Later, the 2010 EFNS/PNS CIDP guidelines included focal CIDP in the list of atypical CIDP as one of its variants [46]. There is, however, no clear evidence from the literature that this form is distinct from LSS and should be kept separate from it. Indeed, three of the nine patients originally described by Thomas et al. [25] had a neuropathy diffused in both upper limbs or lower limbs in a multi-neuropathic fashion whereas other authors included patients with a CIDP restricted to one limb under LSS [19]. There is also no evidence that focal CIDP has a different response to therapy compared with typical CIDP or LSS (Table 3). In the 2021 EFNS/PNS CIDP diagnostic ]. The reported response to therapy and particularly to high-dose IVIg in LSS vary among studies, although in most of them is reported to be unsatisfactory [6,7 && ,20,24]. Some authors reported a reduced response to steroids [14,18,20,24]. Disability in patients with LSS is generally lower than that of patients with typical CIDP [5,6,7 && ,9,10,23].

Pure motor chronic inflammatory demyelinating polyneuropathy
Pure motor CIDP was initially defined as a pure motor symmetric polyneuropathy [30,31]. Subsequently, some authors have included in its definition the electrophysiological criterion of normal sensory nerve conduction studies whereas others have admitted the presence of mild sensory symptoms [32,37]. As for pure sensory CIDP, the 2021 EFNS/PNS guidelines has now subclassified pure motor CIDP in a subform with normal sensory nerve conduction studies ('pure motor CIDP') and in another with abnormal sensory nerve conduction studies ('motor-predominant CIDP') [49 && ]. Some of the initial reports of this clinical entity reported unresponsiveness or worsening with steroids while having an excellent response to IVIg [16,31,32] ( Table 4). This early reports led to the 2010 EFNS/PNS guidelines in recommending IVIg as the initial treatment in pure motor CIDP [46]. A few subsequent studies have, however, not confirmed this early finding [7 && ,33]. In a large Italian study, 43% of the patients with pure motor CIDP responded to steroids (versus 51% of typical CIDP patients) [7 && ], whereas another study reported a response of 80% [33]. It has emerged from the data of the Italian CIDP database that none of the pure motor CIDP patients with normal sensory nerve conduction studies improved with steroid therapy whereas all improved patients had abnormal sensory conduction studies [7 && ]. This finding, which was later confirmed by others [33], suggest that the electrophysiological involvement of sensory fibers is a marker of good response to steroids. It is possible, although speculative, that at least some of the patients with normal sensory electrophysiological studies have multifocal motor neuropathy, which typically is steroidresistant. The 2021 EFNS/PNS CIDP guidelines has, however, confirmed the recommendation to consider IVIg as the initial therapy for pure motor CIDP [49 && ].

Pure sensory chronic inflammatory demyelinating polyneuropathy
The clinical boundaries between pure sensory CIDP and sensory DADS are not well clear, and this may possibly explain why in some studies, patients with a pure sensory neuropathy with a 'stocking-andglove distribution' are included under DADS while in others under pure sensory CIDP [1,34,50]. This confusion probably underlies the large variability in the reported frequency of pure sensory CIDP among studies (1-24%) ( Table 5). An Italian study proposed criteria for atypical CIDP in which sensory DADS was defined as a length-dependent neuropathy whereas sensory CIDP as a nonlength-dependent [7 && ]. In this study, patients with sensory DADS but not those with pure sensory CIDP had a lower response to treatment compared with typical CIDP [7 && ]. This figure has not yet been confirmed by other studies.
Although defined as a pure sensory neuropathy, most of the pure sensory CIDP cases so far described had subclinical electrophysiological involvement of the motor fibers but this is likely to be explained by the fact that signs of demyelination in the motor nerves were required by the 2010 EFNS/PNS diagnostic criteria for the diagnosis of CIDP [46]. Some descriptions of pure sensory CIDP without electrophysiological involvement of motor fibers have, however, been made [51]. In order to provide greater clarity, the 2021 EFNS/PNS criteria has now subclassified pure sensory CIDP in a subform with normal motor nerve conduction studies ('pure sensory CIDP') and in another with abnormal motor nerve conduction studies ('sensory-predominant CIDP') [49 && ]. No studies have yet compared the clinical and immunological characteristics of these two CIDP subforms.
Response to treatment in pure sensory CIDP is reported to be similar to that of typical CIDP Chronic immune sensory polyradiculoneuropathy, chronic immune sensory polyradiculoneuropathy-plus, chronic immune motor polyradiculoneuropathy, and chronic immune-mediated sensorimotor polyradiculopathy CISP is generally considered pure sensory CIDP because of its similar clinical presentation characterized by only sensory symptoms without weakness [41]. Its peculiar feature is the selective involvement of the preganglionic root as evidenced by normal sensory nerve conduction studies, increased CSF protein levels, and thickened spinal roots at MRI [41]. It is a rare CIDP variant; in an Italian study on 460 CIDP patients, its frequency was 0.5% [7 && ]. In the first description of 15 patients, all the patients had ataxia, nine had frequent falls, and six were  severely disabled [41]. All of the treated patients had a rapid improvement, but relapsed on attempted tapering [41]. CISP-plus is a recently described variant in whom the disease extends beyond dorsal roots to also involve motor and postganglionic sensory nerve fibers, resulting in mild distal weakness and mild abnormalities on nerve conduction studies [42 & ]. Its symptoms and response to therapy seem very similar to those of CISP [42 & ]. CIMP is a chronic pure motor polyradiculopathy affecting the lumbosacral segments and sparing sensory, bowel, and bladder functions [43]. Imaging demonstrates nerve root enlargement of the cauda equina, and CSF protein are elevated [43]. To our knowledge, only one patient with CIMP has been reported so far. Eleven patients with an immune-mediated sensorimotor polyradiculopathy (CISMP) have been reported by two different reports [44,45 & ]. Electrophysiological studies were normal in all these patients and a good response to treatment was observed in most of them [44,45 & ]. Although all these rare forms were proposed by the authors as being part of the CIDP spectrum, the 2021 EFNS/PNS criteria mentioned only CISP and specified that it cannot still be considered as CIDP as there is not enough evidence to determine if it is demyelinating or related to sensory CIDP [49 && ].

DIAGNOSIS OF ATYPICAL CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY
As for typical CIDP, no diagnostic biomarker exist for atypical CIDP making clinical and electrophysiological criteria essential for diagnosis. The 2021 EFNS/PNS criteria refined the diagnostic criteria for the CIDP variants and expanded the 2010 EFNS/PNS criteria by including sensory nerve conduction studies as a mandatory diagnostic criterion and by defining specific clinical and electrophysiological criteria for each CIDP variant [49 && ]. Validity of these diagnostic criteria remains, however, to be established. Furthermore, these criteria still leave some areas of uncertainty. For instance, it is not clear how to classify patients with asymmetric but not multineuropathic CIDP or patients with a sensorimotor polyneuropathic CIDP only involving the proximal and distal segments of the lower limbs.
Atypical CIDP is a challenging diagnosis and its diagnostic workflow and differential diagnosis may differ compared with typical CIDP [52 & ]. In one series of misdiagnosed patients, 44% of the patients misdiagnosed as CIDP were found to satisfy the EFNS/PNS criteria but they were all classified as 'atypical' [53]. Compared with the patients with typical CIDP, those with atypical CIDP more frequently were diagnosed in a university hospital and have a diagnostic delay [53,54 & ]. This lead to a greater disability and more frequent fatigue and treatment dependency [54 & ]. Patients with atypical CIDP phenotypes are also more likely to be falsely labelled as having CIDP (overdiagnosis) [52 & , 55]. The reasons that may explain this diagnostic difficulty include the scarce adherence to the EFNS/PNS criteria, the inability to recognize the distinctive clinical and electrophysiological signs of CIDP and the clinical parameters indicative of a true response to therapy [52 & ,53,55]. Given the complexity of the disease and its rarity, several authors have proposed that patients with an atypical CIDP phenotype or with an unexpectedly poor treatment response should be referred to CIDP expertise centres [52 & ,55]. The 2021 EFNS/PNS guidelines have improved guidance regarding the diagnosis of CIDP in general and the specific diagnosis of the individual variants by suggesting a list of other conditions to be considered in the differential diagnosis and a series of diagnostic tests to be performed to exclude other causes [49 && ].

CLINICOPATHOLOGICAL CHARACTERISTICS OF THE CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY VARIANTS
Although the cause of CIDP and its pathogenesis are still unknown, in the last years some progress has been made in deciphering the pathogenetic mechanisms underlying the disease. Several recent lines of evidence suggest that typical CIDP and its variants potentially have heterogeneous pathogenetic mechanisms.
Electrophysiological studies have shown that the distribution of lesions in the peripheral nervous system is different among the individual CIDP forms [ ]. This might also explain why in LSS, the increase in CSF protein levels, which indicates the presence of lesions at proximal nerve segments, is less frequent and conspicuous. In support of this view, different magnetic resonance and ultrasound studies demonstrated hypertrophy predominantly in the nerve roots in patients with typical CIDP and patchy swelling of the nerve trunk in patients with LSS [57]. Similar findings have emerged from recent sural nerve biopsy studies, which showed the presence of uniform alterations with relative preservation of myelinated fibers and few axonal sprouts and onion-bulb formation in patients with typical CIDP, and instead, focal signs of demyelination with marked variation in the density of myelinated fibers among fascicles and conspicuous axonal sprouts in those with LSS [8 && ]. The hypothesis, raised by some authors on the basis of these findings, is that in typical CIDP, the damage occurs in the proximal and distal portions of the nerve where the bloodnerve barrier is most deficient, and therefore, is likely mediated mainly by antibodies and humoral factors [6,8 && , 10,56 & ]. Notably, the 2021 EFNS/PNS CIDP guidelines proposed not to regard patients with antibodies against nodal-paranodal cell-adhesion molecules as CIDP variants as they have distinct clinical features, no overt inflammation or macrophage-mediated demyelination and do poorly respond to CIDP treatment, IVIg, in particular [5]. On the other hand, in LSS, the damage is likely mediated by T cells and macrophages that attack focal portions of the nerve with blood-nerve barrier breakdown [

CONCLUSION
Although the validity of the 2021 EFNS/PNS criteria for CIDP has not yet been assessed, they will lead to greater uniformity in the selection of patients to be enrolled in future studies and this, hopefully, will result in greater comparability of studies. Their implementation should also lead to an improvement in diagnostic accuracy. There are still, however, areas of uncertainty in the definition of the individual variants. Recent studies are starting to bring to light the pathogenetic mechanisms of the individual CIDP variants and this could result in the discovery of specific diagnostic biomarkers and new therapies.